title: Mitochondrial Cu,Zn-superoxide dismutase mediates pulmonary fibrosis by augmenting H2O2 generation.
abstract: The release of H(2)O(2) from alveolar macrophages has been linked to the development of pulmonary fibrosis, but little is known about its source or mechanism of production. We found that alveolar macrophages from asbestosis patients spontaneously produce high levels of H(2)O(2) and have high expression of Cu,Zn-superoxide dismutase (SOD). Because Cu,Zn-SOD is found in the mitochondrial intermembrane space (IMS), we hypothesized that mitochondrial Cu,Zn-SOD-mediated H(2)O(2) generation contributed to pulmonary fibrosis. Asbestos-induced translocation of Cu,Zn-SOD to the IMS was unique to macrophages and dependent on functional mitochondrial respiration and the presence of at least one of the conserved cysteines required for disulfide bond formation. These conserved cysteine residues were also necessary for enzyme activation and H(2)O(2) generation. Cu,Zn-SOD-mediated H(2)O(2) generation was inhibited by knockdown of the iron-sulfur protein, Rieske, in complex III. The role of Cu,Zn-SOD was biologically relevant in that Cu,Zn-SOD(-/-) mice generated significantly less H(2)O(2) and had less oxidant stress in bronchoalveolar lavage fluid and lung parenchyma. Furthermore, Cu,Zn-SOD(-/-) mice did not develop pulmonary fibrosis, and knockdown of Cu,Zn-SOD in monocytes attenuated collagen I deposition by lung fibroblasts. Our findings demonstrate a novel mechanism for the pathogenesis of pulmonary fibrosis where the antioxidant enzyme Cu,Zn-SOD translocates to the mitochondrial IMS to increase H(2)O(2) generation in alveolar macrophages.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine,University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: He
authors.forename: Shubha
authors.initials: S
authors.lastname: Murthy
authors.forename: Michael L
authors.initials: ML
authors.lastname: McCormick
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001194:Asbestos / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D024101:Mitochondrial Proteins; D018384:Oxidative Stress; D021381:Protein Transport; D011658:Pulmonary Fibrosis / Q000209:etiology*; D013482:Superoxide Dismutase / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D024101:Mitochondrial Proteins; D001194:Asbestos; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase